Insulin-dependent diabetes mellitus (IDDM) is a disease resulting from the autoimmune destruction of the insulin-producing .beta.-cells of the pancreas. Studies directed at identifying the autoantigen(s) responsible for .beta.-cell destruction have identified several candidates, including insulin (Palmer et al., Science 222: 1337-1339 (1983)), a poorly characterized islet cell antigen (Bottazzo et al, Lancet ii: 1279-1283 (1974)) and a 64 kDa antigen that has been shown to be glutamic acid decarboxylase (Baekkeskov et al., Nature 298: 167-169 (1982); Baekkeskov et al., Nature 347: 151-156 (1990)). Antibodies to glutamic acid decarboxylase (hereinafter referred to as "GAD") have been found to be present in patients prior to clinical manifestation of IDDM (Baekkeskov et al, J. Clin. Invest. 79:926-934 (1987)).
GAD catalyzes the rate-limiting step in the synthesis of .gamma.-aminobutyric acid (GABA), a major inhibitory neurotransmitter of the mammalian central nervous system. Little is known with certainty regarding the regulation of GAD activity or the expression of GAD genes. Despite its wide distribution in the brain, GAD protein is present in very small quantities and is very difficult to purify to homogeneity. GAD has multiple isoforms encoded by different genes. These multiple forms of the enzyme differ in molecular weight, kinetic properties, sequence (when known), and hydrophobic properties. For example, the presence of three different forms of GAD in porcine brain has been reported (Spink et al., J. Neurochem. 40:1113-1119 (1983)), as well as four forms in rat brain (Spink et al., Brain Res. 421:235-244 (1987)). A mouse brain GAD (Huang et al., Proc. Natl. Acad. Sci. USA 87:8491-8495 (1990)) and a GAD clone isolated from feline brain (Kobayashi et al., J. Neurosci. 7:2768-2772 (1987)) have also been reported. At least two isomers of GAD have been reported in human brain (Chang and Gottlieb, J. Neurosci. 8:2123-2130 (1988)). A human pancreatic islet cell GAD has recently been characterized by molecular cloning (Lernmark et al., U.S. patent application Ser. No. 07/702,162; PCT publication WO 92/20811). This form of GAD is identical to one subsequently identified human brain isoform (Bu et al., Proc. Natl. Acad. Sci. USA 89:2115-2119, 1992). A second GAD isoform identified in human brain is not present in human islets (Karlsen et al., Diabetes 41:1355-1359, 1992).
For at least the first decade of their disease, non-insulin-dependent diabetes (NIDDM) patients are generally treated with oral hypoglycemic agents and/or controlled diet. IDDM and classic NIDDM are generally agreed to have distinct pathegeneses, with only the former being autoimmune in nature. However, IDDM occurs more frequently in patients with a strong history of NIDDM than in the general population (Dahlquist et al., Diabetologia 32:2-6 (1989)), i.e. a significant population of NIDDM patients actually have autoimmune etiology and would be more accurately classified as IDDM. These patients eventually require insulin therapy. Since effective autoimmune intervention strategies for IDDM will probably exist soon, identification of autoimmune diabetes before clinical onset is critically important. Accurate classification of diabetes type may also guide glucoregulatory therapy. Furthermore, loss of functional islet cell mass is slowed in IDDM by treatment with exogenous insulin (Keller, Diabetes 41 (Suppl. 1), xvi, 1992). There is therefore a need in the art for methods of determining the presence of IDDM before clinical onset, including the diagnosis of incipient IDDM in individuals classified as NIDDM. The present invention provides such methods, as well as other, related advantages.